Olefin metathesis is one of the most flexible ways to make carbon-carbon bonds in general and double bonds (C═C) in particular (1, 2, 3). The reaction formally cleaves two different carbon-carbon double bonds (C═C) into four fragments that are recombined into two new C═C double bonds to form olefinic products in which the original fragment partners are exchanged. The last years have seen an almost explosive increase in the use of this reaction for the production of fine chemicals, polymers and pharmaceuticals. The product of this transformation is in general a mixture of cis (Z) and trans (E) disubstituted isomers, with the thermodynamically more stable E-isomer usually being the major component. However, in certain instances the target product is either the pure E- or the pure Z-isomer.
For example, the biological, chemical and physical properties within a given pair of E- and Z-isomers may, in fact, be very different, highlighting the need for selective production of single isomers. The isomer mixtures produced have to be subjected to costly separation processes. Sometimes, the separation may be very challenging (4).
Catalysts for olefin metathesis have evolved rapidly in the past few decades. The catalyst is the main key to controlling the ratio with which the isomers are formed and the availability of robust and industrially compatible stereoselective catalysts is expected to expand the applicability of olefin metathesis in organic synthesis and polymerisation chemistry (3). Such catalysts would have a particular impact on the synthesis of large macrocycles by ring closing metathesis (RCM), strereoregular polymers (ROMP), and stereisomeric pure alkenes. The Z-alkene functionality is, in fact, required in many cases, either because it is present in the target molecule or because it is necessary for subsequent stereospecific transformations. A range of natural products with biological activity (e.g. anticancer, antibacterial, and antifungal) contain Z-alkene macrocyclic frameworks, see Table 1. In most of the cases, the cost of extraction of these molecules is prohibitive, and total synthesis is the only alternative (4, 5). The formation of such large rings is very challenging, with RCM standing out among the few alternative routes (1, 5, 6).
The stereochemical outcome depends on many factors such as the nature of the substrate and of the catalyst, the reaction conditions and on the presence of specific additives (7-10). Time consuming and very costly empirical approaches are therefore required to improve the process of manufacturing the individual molecules. Hence, the quest for efficient stereoselective catalysts is to a large extent driven by commercial needs (3).
In recent years, several highly Z-selective catalysts have been discovered. The first examples were disclosed by Schrock and Hoveyda (11-14). These catalysts are based on molybdenum or tungsten and are capable of promoting metathesis transformations such as ring opening/cross metathesis (ROCM) (12), ring opening metathesis polymerisation (ROMP) (13), olefin homocoupling (14), cross-metathesis (CM) (15, 16), and RCM (17, 18).
More recently highly Z-selective ruthenium-based catalysts have been discovered. Grubbs and co-workers have developed Ru-catalysts involving a bidentate N-heterocyclic carbene (NHC)-adamantyl ligand. These catalysts have shown high selectivity in several processes: cross-metathesis (CM) (19), olefin homocoupling (20, 21), ring opening metathesis polymerisation (ROMP) (22, 23), ring closing metathesis (RCM) (24, 25), and ring opening/cross-metathesis (ROCM) (26). A different system, containing one 2,4,6-triphenylbenzenethiolate ligand has so far demonstrated high Z-selectivity in homocoupling reactions (27, 28). Hoveyda and coworkers have developed another highly Z-selective system containing a dithiolate ligand (29), which has been applied in ring opening metathesis polymerisation (ROMP) and ring-opening/cross-metathesis (ROCM).
U.S. Pat. Nos. 5,312,940, 5,342,909, 5,969,170, 6,111,121, 6,635,768 and 6,613,910, international patent applications WO 98/21214, WO 00/71554 and WO 2004/112951 disclose pentacoordinated ruthenium and osmium olefin metathesis catalysts. The content of those documents is herein incorporated by reference. These catalysts have the general structure:

wherein M is the metal, L and L1 are neutral ligands, R1 and R2 are H or organic moieties and X and X1 are anionic ligands.
Similarly, hexacoordinated ruthenium and osmium olefin metathesis catalysts have also been disclosed, in U.S. Pat. No. 6,818,586 and US patent application US 2003/0069374. The content of those documents is herein incorporated by reference. These catalysts have the general structure:
wherein M is the metal, L, L1 and L2 are neutral ligands, R1 and R2 are H or organic moieties and X and X1 are anionic ligands.
In both the pentacoordinated and the hexacoordinated catalysts the two anionic ligands X and X1 are preferably selected from halide and carboxylate anions. None of these catalysts, however, exhibit significant Z-stereoselectivity.
U.S. Pat. No. 7,094,898 and US patent application US 2005/0131233 disclose ruthenium-based olefin metathesis catalysts with a high rate of catalytic turnover and a high degree of stability. The content of those documents is herein incorporated by reference. The catalysts described in these documents have anionic ligands with the structure Z-Q, wherein each Z may comprise O, S, N or C and each Q comprises a planar electron-withdrawing group.
These documents also describe three novel asymmetrically substituted complexes Ru(OC6Cl5)Cl(CHPh)(IMes(py), Ru(OC6Br5)Cl(CHPh)(IMes)(py) and (Ru(OC6Br5)Cl(CHPh)(IMes)(3-Br-py) that display a weak Z-stereoselectivity in the RCM of 5-hexen-1-yl 10-undecenoate to give oxa-cyclohexadec-11-en-3-one (Exaltolide). The product obtained using these catalysts contains 9-12% more of the Z-isomer than when using a symmetrically substituted catalyst. However, the Z-stereoselectivity of these asymmetrically substituted catalysts turns out not to be general. For example, in another RCM reaction reported in the same patent, the percentage of the Z-isomer product obtained using the asymmetrically substituted catalysts Ru(OC6Cl5)Cl(CHPh)(IMes)(py) and Ru(OC6Br5)Cl(CHPh)(IMes)(py)) is very similar to that obtained using two symmetrically substituted catalysts, RuCl2(CHPh)(IMes)(py2) and Ru(OC6F5)2(CHPh)(IMes)(py).
These documents also report a ruthenium olefin metathesis catalyst with an anionic ligand in which a sulphur atom is bound to ruthenium (Ru(SC6F5)2(CHPh)(IMes)(py)). However, only partial characterisation, consisting of 1H-NMR and 19F NMR spectra, is provided for this compound. This catalyst displays good catalytic activity, surpassing that of the corresponding oxygen-based catalyst Ru(OC6F5)2(CHPh)(IMes)(py), for example in the RCM of the 1,9-decadiene to give cyclooctene. However, no particular E/Z stereoselectivity is reported for this catalyst.
WO 2012/032131 describes Z-stereoselective olefin metathesis catalysts based on ruthenium- and osmium metal complexes. The content of this document is herein incorporated by reference. In olefin metathesis reactions, the described catalysts selectively provide the thermodynamically less favoured Z-isomers.
EP 2 826 783 A1 describes ruthenium and osmium complexes for use as catalysts in olefin metathesis reactions. In addition to being Z-selective, the described catalysts provide superior stability in air and under protic conditions. In contrast to other Z-selective catalysts, they are able to effect Z-selective olefin metathesis in air, using non-degassed (i.e. stored under air) olefinic substrates and solvents.
However, there still remains a need for improved Z-selective catalysts with high catalytic activity and stability. In particular, there is a need for fast initiating catalysts that can promote olefin metathesis transformations within a broad range of temperatures. Further, there is a need for Z-selective catalysts with high olefin metathesis selectivity, i.e. low tendency to isomerization of the olefinic substrate.
The present invention addresses the above need for highly active and stereoselective olefin metathesis catalysts by providing a novel class of ruthenium-based catalysts.